The architectural complexity of the retina is brought about by a series of developmental events controlling" proliferation, fate determination, migration, process outgrowth, target recognition, synaptogenesis and cell death. These processes establish a precisely layered structure in which retinal neurons become positioned at different depths, connected via two intervening synaptic layers. Superimposed upon this layered organization, certain cell types are distributed as orderly arrays across a given layer so that they, and their processes, ensure a uniform sampling of the retinal surface as they establish connectivity with their afferent and target neurons. This research program is seeking to understand the cellular, molecular and genetic determinants of this patterning and connectivity in such arrays, focusing upon the population of horizontal cells. A quantitative trait analysis of horizontal cell number in recombinant inbred strains will first identify genes that control the size of this neuronal population. Chimeric mice will be produced from parental strains that differ in horizontal cell number, to determine whether dendritic field size is controlled by cell-intrinsic vs environmental instructions. A comparable quantitative trait analysis of the cone photoreceptors will also be conducted, and the role played by the afferents in specifying dendritic patterning of horizontal cells will be examined in various knockout and recombinant inbred strains in which the convergence ratio between cones and horizontal cells is modulated, or in which neurotransmissionbetween these afferents and the dendrites is altered or abolished. The roles played by both homotypic neighbors and by afferents in the establishment of this connectivity will be determined, examining the hypothesis that the onset of visual activity drives a competitive interaction between neighboring horizontal cells as they seek to colonize individual pedicles in the developing outer plexiform layer. Microarray analysis of embryonicretina from .two parental strains . showing a two-fold difference in both horizontal and cone cell number will be used to identify downstream genes critical for the establishment of these differences. These experiments will reveal the genes that regulate horizontal and cone cell number, as well as the biological mechanisms by which horizontal cells establish their morphological patterning, dendritic coverage and connectivity with cone afferents during development.